Lactones of the saturated and unsaturated cyclopentanopolyhydrophenanthrene series and process of preparing same



Patented Nov. 7, 1944 UNITED STATES PATENT iOF-FICE LACTONES or THE SATURATED AND UNSATURATED CYCLOPENTANOPOLY- HYDROPHENANTHRENE SERIES AND rnoonss F PREPARING ,SAME

Leopold Ruzicka, Zurich, Switzerland, assignor to Ciba Pharmaceutical Products Inc., Summit N. J., a corporation 'No'Drawing. 7 Application April 29, 1942, Serial No. 441,032. 'In Switierland May;31,1941

20 Claims.

The aglycones of most vegetable cardiac poisons are derivatives of the cyclopentanopolyhydrophenanthrene series which are characterized by possessing an unsaturated lactone ring in 17-position.

This invention r'elates to the manufacture of such lactones of the saturated and unsaturated cyclopentanopolyhydrophenanthrene series by condensing a compound of the said series having a side chain of the formula inwhich A stands for an aliphatic hydrocarbon radical, Y is a member of the group consisting of hydrogen and alkyLand R stands for a free,

esterified or etherified hYdIO'XYl group with a functional derivative of a halogen fatty acid, such as an mor p halogenated fatty acid ester,

amide or nitrile and if desired subjecting the condensation product to a re-esterifying treat ment and/or a treatment for splitting off water.

The parent materials can be easily obtained, for example by starting from bile acids, such as cholanic'acid and desoxy-cholanic acid or from their degradation products, or from degradation products of othernatural sterols and steroids.

Examples of such materials are the'3z'7z12-trioxy-norcho1a'nyl-(23) oxymethyl-ketone I y C OGH2O 0 The condensation may be"efiected in'known manner by means of metals, such as zinc orma'gnesiu'm; in" a "suitable inert solvent,for instance benzene, toluene, dioxane or ether. Lactohization generally occurs. during the condensation and also frequently a partial elimination of water. "When lactonization takes place only with diflicult'y a treatment'with re esterifying or hy-, drolyzingand lactonizing agentswmay 'be advantageous. In manyinstanc'e'sone obtains mixtures which may be separated :into their constituents or further worked uplas mixtures. Thus; if desired the condensation-product,may be subjected to theknown treatments: for eliminating water, of which distillation or sublimation under diminished pressure has: proved :especially :useful, ,if

desired after admixturecwith surface-active sub;-

s'tances, for instancelaluminium oxide, silica gel,

active carbon, fullersearth orwith an anhydrous salt,'forinstance copper sulfate. The mixtureproduced of 'lactones may be treated for isolating pure components in the,usua1..manne r, for instanceb fractional crystallization or by chromatographic adsorptionanalysis.

The products obtained bythis process are 5- or G-membered saturated? hydroxylactones or unsaturated lactones which possess between the lactone ring and the; cyclopentanopolyhydrophenanthrene nucleusiani aliphatic radical, for instance an alkylene group; asdescribed above.

The followingmexamples illustrate-the inven tionbut arenot to be-regarded as limiting it in any way:

Example 1 2.0 gr. of 3:7:12-triacetoxy-nor-cholanyl (23) aoetoxy-methylketone of the formula OCbCHa CH 10H. Cm 7 H 12 I 7 CHzO C OCH: 0 C OCH:

acetylated with acetic anhydride prior to the further working up. The crude mixture of lacis obtained as main product. The corresponding free 3:7:12-trihydroxy-compound can be obtained by acid saponification.

Example 2 N -3-acetoxy-Z5-diazo-26:27 bisnor cholestene-Zl-one (obtained for'example according to Chemisches Zentralblatt, 1939, I, 1182, 1372) are converted by boiling in pure glacial acetic acid into the A -3:25-diacetoxy-26:27-bisnorcholestene-Zl-one of melting point 126 C. and [a]D=-4=5 C. (chloroform) 5.9 gr. of this diacetoxyketone and 9.5 gr. of activated zinc spangles are dried in a high vacuum. 80 com. of dry benzene are added and about /3 of the solvent is distilled for drying the apparatus. 18 gr. of ethylbromacetate dissolved in 20 com. of absolute dioxane are added and the whole is heated in a reflux apparatus until the vigorous reaction sets in. After this has ceased, the solution is diluted with 150 com. of absolute alcohol and filtered to remove the zinc which has not been consumed. For completing the the lactonization 40 com. of concentrated hydrochloric acid are added to the filtrate and boiling on the water-bath is continued for a short time. After cooling, the whole is diluted with water and the reaction product is taken up in ether. When concentrating the ether solution to a small volume, the larger portion of the reaction mixture is crystallized. By suction filtering there is obtained a product which behaves negatively in the legal test. It consists essentially of B-[A -3-hydroxy-nor-cholenyl- 23) l-flw-dioxy-n-butyric acid v-lactone and its 1 nor-cholenyl-(23)l-butenolide of melting point 229-230 0., of specific rotation [aln=42.5

f (chloroform) and of the formula CH5 CH3 CH3 I CH(CH2)2C='=CH p 1 H2 o o is obtained therefrom in practically quantitative yield. The product yields a positive legal test and has an absorptive maximum at about 220 my. (log.=4.1).

When using a bromopropionic acid ester instead of a bromoacetic ester, the corresponding butenolide methylated in (wt-position is obtained. Also higher halogen fatty acid derivatives produce the corresponding a-alkylated butenolides.

When starting from A -3:25-diacetoXY- nor-cholestene-Z l-one (obtained by reaction of A -3-acetoxycholenic acid chloride with diazoethan and subsequent boiling with glacial acetic acid) analogous products which carry a methyl group in 'y-position are obtained.

Example 3 2.0 gr. of A -3hydroXy-17-[l'7 -acetoxy-17 oxo-propyll-androstene of melting point 138-139 C. of the formula (obtained for example from A ="-3-hydroxypregnadiene-2l-acid of melting point 249-250 C. by acetylation and reaction with thionylchloride, allowing diazomethane to act on the mixture and subsequent alkaline saponification of the diazoketone obtained by splitting off the acetyl group in B-position, heating with glacial acetic acid and selective hydrogenation of the monoacetate formed by saturating the 17:20-double bond with Raney-nickel in rectified alcohol) are dissolved in 30 com. of absolute benzene and the solution is caused to react with 2.0 gr. of ethylbromacetate dissolved in 10 com. of dioxane and 4.0 gr. of zinc-copper. A spontaneous reaction soon sets in, and when this has ceased the reaction mixture is heated for a short time in a. reflux apparatus. The reaction mixture is then diluted with methanol. Th whole is filtered to remove the unchanged zinc, concentrated to a large degree and decomposed with aqueous hydrochloric acid. The solution obtained is boiled for a short time and, after cooling, the reaction product is taken up in ether. After concentrating the ethereal solution the residue is boiled for some hours with acetic anhydride. The anhydride in excess is evaporated in a vacuum, whereby the crude A -13-[A -3-acet0xy21-norpregnenyl-(20) l-butenolide of the formula the radical by the same fln'al' product isbbtained. Instead of ,etnyibromacetatetner ayaiso )be used other halogen-acetic acid esters aswenas further runctional derivatives or aor smalo 'en fatty acids,

such as bromo-acetamide or 'bromo-acetonitriie.

1. In a process the manufacture of a la'ctone or the cycldpentanopolyhydrophenanthrene series, the step or reacting a compound of the wherein A stands ro: an aliphatic hydrocarbon radical containing'at least one and no more than 4 carbon atoms, Y is a'merriber' of the group consis'tiiig of hydrogen and alkyl, and'Rfstands for a member of the group consistingo'f free', ester'ilied and etherifledhydroxyl, with a "member of the groupconsi'sting' of the esters, amides and nitriles Of the dand ii-halogen fatty acids". in presence of "a' metal condensing agent.

2. Ina process tor the manufacture of a labto'he of the 10:13-'diiriethyl=cyc1opentanopo1yhydro- Hpheiianthrene' series, the step of reacting a compound of the said series having in iii-position wherein A stands for an aliphatic hydrocarbon; :f vthe y p nt n lyhydfQ h fl flfhfe ne radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and alkyl, and R stands for a member of the group consisting of free, esterifled and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the aand fl-halogen fatty acids, in presence of a metal condensing. agent;

' 3. In a; process for the manufacture of a lactone of the l0:.13-dimethyl-cyclopentanopolyhy- .drophenanthrene series, the step of reacting a ,"the group consisting of the esters of the aand shalogen fatty acids; in presence of a metalcons I .den'sing agent.

4. In a process for the manufacture of a lactone of the 110:13-dimethy1-cyclopentanopolyhyidrophenanthrne series,-the step of reacting a 1 compound of the said series having the radical Y Y ACO-*CH wherein A stands for an aliphatic hydrocarbon radical containing at least one andnomore than 4 carbon atoms, .Y is a member of the group consisting of hydrogen and alkyl, and R stands for a member of the group consisting "of free, estiified' in 17-position" phenant'hrene series, the step of reacting 18 4:25- d'iacetoxy- 26527 hisnorcholestene-24-one with tone of the cyc1opentanopolyhydiophenanthrene series, the steps of reacting a compound of the f ethylbromoacetate' in presence of a metal con- "and-etherified iiyardiryig was :etnyitr'omoacetate, in presence-tr sheet-1 eoadensingagent. i

condensing agent.

' .6. In a process for-the manufacture of a lactone of the unsaturated cycldpehtanopolyhydrm densing a'gent.

7. In a processfor the manufacture of a 1830- said series having in 17-positio'r'1 the radical I A-C'OL'-:l

. i R wherein A stands fo-r an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and alkyl, and R stands for a member of the group consisting of free, esterified group consisting of'the esters, amides and nitriles of the aand [i -halogen fatty acids, in presence or a, metal condensing agent, arid then subjecting the resultant condensation product to a process for eliminating water. t

8. A process for the manufacture of a lactdne ries, which comprises reacting a compound or the 'said series hailing in 'l7-positidii the radical I wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogenand alkyl, and R stands for a member of the group consisting of free, esterified and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the sand B-halogen fatty acids in jetting the condensation product to a process for j eliminating water, and lactonizirig agent.

then to the ac'tiondr a 9. A process for the; manufacture of a lactone for thecyclopentanopoiynydropnenanthrene series,

, wl'iich comprises reacting a com ound of the said series having in I'T-pbsition the radical R wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and akyl, and R stands for a member of the group consisting of free, esterified and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the aand p-halogen fattyacids in presence 0:

ing water, and then tothe action of a hydrolyzing agent, laetonizin'g. agent and re-es'terifying agent;

' 10. A'prdcess for the" manufacture or a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting a compound of the said series having in l'l-position the radical wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group con wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and alkyl, and R stands for a, member of the group consisting of free, esterified and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the c-and B-halogen fatty acids in presence of a metal condensing agent, and sub- J'ecting the condensation product to the action of a hydrolyzing agent and a lactonizing agent.

12. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting a compound of the said series having in l7-position the radical wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and alkyl, and R stands for a member of the group consisting of free, esterified and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the aand B-halogen fatty acids in presence of a metal condensing agent, and subjecting the condensation product to the action of a hydrolyzing agent, lactonizing agent and re-esterifying agent.

13. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting a compound of the said series having in 17-position the radical wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and alkyl, and R stands for a member of the group consisting of free, esterified and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the aand ti-halogen fatty acids in presence of a metal condensing agent, and subjecting the condensation product to the action of a lactonizing agent and then to a process for eliminating I water.

14. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting a compound of the said series having in 17-position the radical wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and alkyl, and R stands for a member of the group consisting of free, esterified and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the aand iii-halogen fatty acids in presence of a metal condensing agent, and subjecting the condensation product, and then to the action of a hydrolyzing agent and a lactonizing agent and then to a process for eliminating water.

15. A process for the manufacture of a lactone of the cyclopentanopolyhydrophenanthrene series, which comprises reacting a compound of the said series having in l'7-position the radical /Y -ACOCH wherein A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms, Y is a member of the group consisting of hydrogen and alkyl, and R stands for a member of the group consisting of free,

esterified and etherified hydroxyl, with a member of the group consisting of the esters, amides and nitriles of the aand B-halogen fatty acids in presence of a metal condensing agent, and subjecting the condensation product to the action of a hydrolyzing agent, lactonizing agent and re-esterifying agent and then to a process for eliminating water.

16. The saturated and unsaturated cyclopentanopolyhydrophenanthrene compounds having in l7-position one of the groupings and in which A stands for an aliphatic hydrocarbon radical containing at least one and no more than 4 carbon atoms.

18. The A"='-p-[3:7:IZ-trihydroxy-nor-cholan- 20. The A'='-p-[A =-3-hydroxy-2l-nor-pregy1-(23)]-butenolide of the formula I nenyl-(20)]-butenolide of the formula OH CH: CH: CE; CH; CH; 5 CH-C----CH "C HCH:-CH:-G==(lJH I H: 0 I k 0 0 I 10 H0 110 CH LEOPOLD RUZICKA.

19. The A -is-[A -3-hydroxy-h0r-cho1nyl- (23) J-butenolide of the formula CH3 CH3 

